Gene Expression and Signaling Lab, Department of Zoology, Mahatma Gandhi Central University, Motihari 845401, Bihar, India.
MIRCADE Team, U1312, Bordeaux Institute in Oncology, BRIC, Université de Bordeaux, 146 Rue Léo Saignat, F-33000 Bordeaux, France.
Int J Mol Sci. 2023 Sep 14;24(18):14066. doi: 10.3390/ijms241814066.
Endoplasmic reticulum (ER) is the site for synthesis and folding of secreted and transmembrane proteins. Disturbance in the functioning of ER leads to the accumulation of unfolded and misfolded proteins, which finally activate the unfolded protein response (UPR) signaling. The three branches of UPR-IRE1 (Inositol requiring enzyme 1), PERK (Protein kinase RNA-activated (PKR)-like ER kinase), and ATF6 (Activating transcription factor 6)-modulate the gene expression pattern through increased expression of chaperones and restore ER homeostasis by enhancing ER protein folding capacity. The liver is a central organ which performs a variety of functions which help in maintaining the overall well-being of our body. The liver plays many roles in cellular physiology, blood homeostasis, and detoxification, and is the main site at which protein synthesis occurs. Disturbance in ER homeostasis is triggered by calcium level imbalance, change in redox status, viral infection, and so on. ER dysfunction and subsequent UPR signaling participate in various hepatic disorders like metabolic (dysfunction) associated fatty liver disease, liver cancer, viral hepatitis, and cholestasis. The exact role of ER stress and UPR signaling in various liver diseases is not fully understood and needs further investigation. Targeting UPR signaling with drugs is the subject of intensive research for therapeutic use in liver diseases. The present review summarizes the role of UPR signaling in liver disorders and describes why UPR regulators are promising therapeutic targets.
内质网（ER）是分泌型和跨膜蛋白合成和折叠的场所。ER 功能障碍会导致未折叠和错误折叠蛋白的积累，最终激活未折叠蛋白反应（UPR）信号。UPR 的三个分支——IRE1（肌醇需求酶 1）、PERK（蛋白激酶 RNA 激活（PKR）样内质网激酶）和 ATF6（激活转录因子 6）——通过增加伴侣蛋白的表达来调节基因表达模式，并通过增强 ER 蛋白折叠能力来恢复 ER 内稳态。肝脏是一个重要的器官，具有多种功能，有助于维持我们身体的整体健康。肝脏在细胞生理学、血液内稳态和解毒方面发挥着多种作用，是蛋白质合成的主要场所。ER 内稳态的紊乱是由钙平衡失衡、氧化还原状态变化、病毒感染等引起的。ER 功能障碍和随后的 UPR 信号参与各种肝脏疾病，如代谢（功能）相关脂肪性肝病、肝癌、病毒性肝炎和胆汁淤积。ER 应激和 UPR 信号在各种肝脏疾病中的确切作用尚不完全清楚，需要进一步研究。用药物靶向 UPR 信号是治疗肝脏疾病的研究热点。本综述总结了 UPR 信号在肝脏疾病中的作用，并描述了为什么 UPR 调节剂是有前途的治疗靶点。
